Pyrrolyl compounds and processes for their manufacture

ABSTRACT

Pyrrolyl compounds of the formula I ##EQU1## wherein Py is optionally lower-alkylated 1-pyrrolyl, Ph is phenylene, R 1  is hydrogen or lower alkyl and R 2  is hydrogen, lower alkyl, aryl-lower alkyl or optionally functionally modified carboxy-lower alkyl or R 1  and R 2  together are lower alkylene, oxa-lower alkylene, thia-lower alkylene or aza-lower alkylene, their antipodes and salts, which are valuable blockers of adrenergic β-receptors.

The invention relates to new pyrrolyl compounds of the formula I##STR1## wherein Py is optionally lower alkylated 1-pyrrolyl, Ph isphenylene, R₁ is hydrogen or lower alkyl and R₂ is hydrogen, loweralkyl, aryl-lower alkyl or optionally functionally modifiedcarboxy-lower alkyl or R₁ and R₂ together are lower alkylene, oxa-loweralkylene, thia-lower alkylene or aza-lower alkylene, and to processesfor their manufacture.

In the preceding and following text, a lower radical is in particularunderstood as a radical with up to 7 C atoms, above all with up to 4 Catoms.

Lower alkyl R₁ and R₂, and lower alkyl as a substituent of pyrrolyl Py,preferably has up to 7 C atoms, above all up to 4 C atoms, such asstraight or branched butyl, pentyl, hexyl or heptyl bonded in anydesired position, but especially n-propyl, ethyl and above all methyl,isopropyl and tert.-butyl and, in the case of a substituent of pyrrolylPy, above all methyl.

Lower alkyl substituents are in particular bonded in the 2- and/or5-position to a l-pyrrolyl radical.

Phenylene Ph is meta-phenylene and especially ortho-phenylene orpara-phenylene.

Aryl-lower alkyl R₂ preferably has up to 12 C atoms, above all up to 10C atoms, and is unbranched or, preferably, branched in the lower alkylpart, and in particular branched at the α-C atom of the lower alkylpart. The aryl part is, in particular, a phenyl radical which isoptionally polysubstituted or, in particular, monosubstituted by loweralkyl, such as the lower alkyl indicated above, lower alkoxy, halogen ortrifluoromethyl, but is preferably unsubstituted. Examples of aryl-loweralkyl R₂ are 1-methyl-3-phenyl-propyl and especially1-methyl-2-phenylethyl.

Lower alkoxy preferably has up to 7 C atoms, above all up to 4 C atoms,and is therefore preferably straight or branched butoxy, pentyloxy,hexyloxy or heptyloxy or above all iso- or n-propoxy, ethoxy or,especially, methoxy.

Halogen is, for example, bromine and especially chlorine.

Optionally functionally modified carboxy-lower alkyl R₂ preferably hasup to 7 C atoms, above all up to 4 C atoms, in the lower alkyl part andis unbranched or preferably branched, in particular branched at the α-Catom. Optionally functionally modified carboxy-lower alkyl is thuspreferably carboxymethyl, 2-(2-carboxy)-propyl, 2-(4-carboxy)-butyl orespecially 2-carboxyethyl or above all 2-(3-carboxy)-propyl functionallymodified at the carboxyl group. The optionally functionally modifiedcarboxyl group is, for example, free, esterified or amidised carboxyl ornitrile.

Esterified carboxyl is, for example, carboxyl esterified with analiphatic alcohol. Aliphatic alcohols are those in which the hydroxylgroup is bonded to a C atom which is not a member of an aromatic system.Suitable aliphatic alcohols are, for example, cycloalkanols, such asthose with 3-7, especially 5-7, ring members, for example cyclopropanol,cyclopentanol, cyclohexanol and cycloheptanol, cycloalkyl-loweralkanols, which contain, for example, the above cycloalkyl parts, suchas cyclopentyl-methanol, cyclohexyl-methanol, 2-cyclohexyl-ethanol andcycloheptyl-methanol, phenyl-lower alkanols, such as 2-phenylethanol andbenzyl alcohol, wherein phenyl radicals can also be substituted byhalogen, lower alkyl and/or lower alkoxy, such as those mentioned above,and especially lower alkanols, such as n-propanol, iso-propanol,straight-chain or branched butanol, pentanol, hexanol or heptanol, andespecially methanol or ethanol. Thus, esterified carboxyl is, above all,methoxycarbonyl or ethoxycarbonyl.

Amidised carboxyl is substituted or unsubstituted carbamoyl. Substitutedcarbamoyl has, for example, the formula -CO-NR₃ R₄, wherein R₃ ishydrogen or lower alkyl, R₄ is lower alkyl or R₃ and R₄ together arelower alkylene, oxa-lower alkylene, thia-lower alkylene or aza-loweralkylene. Lower alkyl in particular has the abovementioned meaning.

Lower alkylene R₃ + R₄, and R₁ + R₂, is branched or, in particular,straight-chain or lower alkylene with, in particular, 2-7, above all4-6, C atoms in the alkylene chain, and in particular represents,together with the N atom to which the lower alkylene is bonded,pyrrolidino or piperidino.

Oxa-lower alkylene R₃ + R₄, and R₁ + R₂, is branched or, in particular,straight-chain oxa-lower alkylene with, in particular, straight-chainoxa-lower alkylene with, in particular, 4 or 5 C atoms in theoxa-alkylene chain, and in particular represents, together with the Natom to which the oxa-lower alkylene is bonded, morpholino.

Thia-lower alkylene R₃ + R₄, and R₁ + R₂, is branched or, in particular,straight-chain thia-lower alkylene with, in particular, 4 or 5 C atomsin the thiaalkylene chain and in particular represents, together withthe N atom to which the thia-lower alkylene is bonded, thiomorpholine or2,6-dimethylthiomorpholino.

Aza-lower alkylene R₃ + R₄, and R₁ + R₂, is branched or straight-chainaza-lower alkylene with, in particular, 2-6, above all 4-6, C atoms inthe aza-alkylene chain, and in particular represents, together with theN atom to which the aza-lower alkylene is bonded, piperazino,N'-methylpiperazino or N'-(β-hydroxyethyl)-piperazino.

The new compounds possess valuable pharmacological properties. Thus theyshow an excitation-inhibiting action, as can be demonstrated ondetermining the pargyline-reserpine antagonism on intraperitonealadministration of doses of about 0.4 to 10mg/kg to mice. The newcompounds therefore are useful for the treatment of states ofexcitation. They block cardiac β-receptors, as is evident from thedetermination of the antagonism to tachycardia when administeredintravenously in doses of 0.01 to 1 mg/kg to narcotised cats that havebeen treated intravenously with 0.5 μg/kg of d/1-isoproterenol sulphate.They also block vascular β-receptors, as is manifest from thedetermination of vasodilatation when administered intravenously in dosesof 0.01 to 1 mg/kg to narcotised cats that have been treated i.v. with0.5 μg/kg of d/1-isoproterenol sulphate, and they also block cardiacβ-receptors, as is clear from the determination of tachycardia whenadministered in a concentration of 0.01 to 1 μg/ml after treatingisolated guinea pig hearts in vitro with 0.005 μg/ml ofd/1-isoproterenol sulphate. The new compounds therefore are useful asblockers of adrenergic β-receptors in the treatment of heart andcirculatory aliments, e.g. arrhythmic disturbances, angina pectoris andhypertension. They can, however, also be used as valuable intermediateproducts for the manufacture of other useful materials, especiallypharmaceutically active compounds.

Compounds to be singled out are compounds Ia of the formula I, whereinPy is optionally mono- or di-lower alkylated 1-pyrrolyl, Ph isphenylene, R₁ is hydrogen or lower alkyl and R₂ is hydrogen, loweralkyl, aryl-lower alkyl, carbamoyl-lower alkyl or cyano-lower alkyl orR₁ and R₂ together are lower alkylene, oxa-lower alkylene, thia-loweralkylene or aza-lower alkylene.

Compounds to be singled out particularly are compounds Ib of the formulaI, wherein Py is optionally mono- or di-lower alkylated 1-pyrrolyl, Phis ortho- or paraphenylene, R₁ is hydrogen or lower alkyl and R₂ ishydrogen, lower alkyl, phenyl-lower alkyl, carbamoyl-lower alkyl orcyano-lower alkyl or R₁ and R₂ together are lower alkylene, oxa-loweralkylene, thia-lower alkylene or aza-lower alkylene.

Compounds which are particularly suitable are compounds Ic of theformula I, wherein Py is 1-pyrrolyl, methyl-1-pyrrolyl ordimethyl-1-pyrrolyl, Ph is ortho- or para-phenylene, R₁ is hydrogen,methyl or ethyl and R₂ is methyl, ethyl, isopropyl, tert.-butyl,α-methyl-phenethyl, carbamoyl-lower alkyl with up to 5 C atoms orcyano-lower alkyl with up to 5 C atoms, or R₁ and R₂ together with the Natom to which they are bonded are pyrrolidino, piperidino, morpholino,thiomorpholinio, piperazino, N'-methylpiperazino orN'-(β-hydroxyethyl)-piperazino.

Compounds to be singled out very particularly are compounds I_(d) of theformula I, wherein Py is 1-pyrrolyl or mono- or di-lower alkylated1-pyrrolyl, Ph is ortho- or para-phenylene, R₁ is hydrogen or loweralkyl and R₂ is lower alkyl or R₁ and R₂ together are lower alkylene,oxa-lower alkylene, thia-lower alkylene or aza-lower alkylene and, inparticular, Py is 1-pyrrolyl or 2,5-dimethyl-1-pyrrolyl, Ph is ortho- orpara-phenylene, R₁ is hydrogen, R₂ is iso-propyl or tert.-butyl or R₁and R₂ together with the N atom to which they are bonded are morpholino,and above all the compounds mentioned in the examples.

The new compounds are obtained according to methods which are inthemselves known.

Thus, for example, a possible procedure is to react a compound of theformula II ##STR2## with a compound of the formula III

    Z.sub.2 -R.sub.1 or Z.sub.2 -R.sub.2                       (III)

wherein Py, Ph, R₁ and R₂ have the above meanings, one of the radicalsZ₁ and Z₂ is --NH-R₂ or --NH-R₁ and the other is reactively esterifiedhydroxyl and X₁ is hydroxyl or, if Z₂ is --NH-R₂ or --NH-R₁, Z₁ togetherwith X₁ is epoxy. However, Z₁ must not denote NH₂.

A reactive esterified hydroxyl group is, in particular, a hydroxyl groupesterified by a strong inorganic or organic acid, above all a hydrogenhalide acid, such as hydrochloric acid, hydrobromic acid or hydriodicacid, or sulphuric acid, or a strong organic sulphonic acid, such as astrong aromatic sulphonic acid, for example benzenesulphonic acid,p-bromobenzenesulphonic acid or p-toluenesulphonic acid. Thus, Z₁ or Z₂in particular represents chlorine, bromine or iodine.

This reaction is carried out in the usual manner. If a reactive ester isused as the starting material. the reaction is preferably carried out inthe presence of a basic condensation agent and/or with an excess ofamine. Examples of suitable basic condensation agents are alkali metalhydroxides, such as sodium hydroxide or potassium hydroxide, alkalimetal carbonates, such as potassium carbonate, and alkali metalalcoholates, such as sodium methylate, potassium ethylate and potassiumtertiary butylate.

A further possible procedure is to react a compound of the formula IV

    Py-Ph-OH                                                   (IV)

with a compound of the formula V ##STR3## wherein Py, Ph, R₁ and R₂ havethe above meanings, Z is a reactive esterified hydroxyl group and X₁ ishydroxyl, or Z and X₁ together form an epoxy group.

A reactive esterified hydroxyl group is, in particular, a hydroxyl groupesterified by a strong inorganic or organic acid, above all a hydrogenhalide acid, such as hydrochloric acid, hydrobromic acid or hydriodicacid, or sulphuric acid, or a strong organic sulphonic acid, such as astrong aromatic sulphonic acid, for example benzenesulphonic acid,p-bromobenzenesulphonic acid or p-toluenesulphonic acid. Thus, Z inparticular represents chlorine, bromine or iodine.

This reaction is carried out in the usual manner. If reactive esters areused as the starting material, the compound of the formula IV canpreferably be used in the form of its metal phenolate, such as alkalimetal phenolate, for example sodium phenolate, or the reaction iscarried out in the presence of an acid-binding agent, especially acondensation agent which can form a salt with the compound of theformula IV, such as an alkali metal alcoholate, hydroxide or carbonate.

A further possible procedure is that in a compound of the formula I,wherein Py, Ph, R₁ and R₂ have the above meanings and which optionallypossesses a removable radical on the nitrogen atom of the --NR₁ R₂ aminogroup and/or on the 2-hydroxyl group, this radical or these radicals isor are removed.

Such removable radicals are, in particular, radicals removable bysolvolysis, such as radicals removable by hydrolysis or ammonolysis orby reduction.

Examples of radicals which can be removed by hydrolysis are acylradicals, such as optionally funtionally modified carboxyl groups, forexample oxycarbonyl radicals, such as alkoxycarbonyl radicals, forexample the tert.-butoxycarbonyl radical or the ethoxycarbonyl radical,aralkoxycarbonyl radicals, such as phenyl-lower alkoxycarbonyl radicals,for example a carbobenzoxy radical, halogenocarbonyl radicals, forexample the chlorocarbonyl radical, and also arylsulphonyl radicals,such as toluenesulphonyl or bromobenzenesulphonyl radicals, andoptionally halogenated, such as fluorinated, lower alkanoyl radicals,for example the formyl, acetyl or trifluoroacetyl radical, or aroylradicals which are optionally substituted like the radical Ph, forexample the benzoyl radical, or nitrile groups or silyl radicals, suchas the trimethylsilyl radical.

Possible radicals, removable by hydrolysis, on the hydroxyl group are,amongst those mentioned, in particular oxycarbonyl radicals, loweralkanoyl radicals and benzoyl radicals.

Compounds with radicals removable by ammonolysis or especially byhydrolysis are, in particular, compounds of the formula VI ##STR4##wherein Py, Ph and R₂ have the above meanings and Y represents acarbonyl or thiocarbonyl radical or, in particular, a divalent radicalof an aldehyde or ketone formally obtainable by replacement of the oxogroup.

Ketones are, for example, di-lower alkylketones, such as methyl ethylketone or acetone, or lower alkyl aryl ketones, such as phenyl methylketone. Aldehydes are, for example, lower alkanals, such as those with,in particular, up to 7 C atoms, such as acetaldehyde or above allformaldehyde, or aryl-lower alkanals, such as phenyl-lower alkanals, forexample benzaldehyde.

The hydrolysis is carried out in the usual manner, for example in thepresence of hydrolysing agents, for example in the presence of acidagents, such as, for example, of an aqueous mineral acid, such assulphuric acid or a hydrogen halide acid, or of an organic acid, forexample a suitable carboxylic acid, such as anα-halogenoalkanecarboxylic acid, for example trifluoroacetic acid orchloroacetic acid, an organic sulphonic acid, for examplebenzenesulphonic acid or toluenesulphonic acid, or of acid ionexchangers, or in the presence of basic agents, for example alkali metalhydroxides, such as sodium hydroxide. Oxycarbonyl radicals,arylsulphonyl radicals and nitrile groups can advantageously be removedby acid agents, such as by a hydrogen halide acid, especiallyhydrobromic acid. The removal by means of aqueous hydrobromic acid,optionally mixed with acetic acid is, for example, particularlysuitable. Nitrile groups are in particular removed by hydrobromic acidat an elevated temperature, such as in boiling hydrobromic acid, by thecyanogen halide method (v. Braun). Further, for example, atert.-butoxycarbonyl radical can be split off under anhydrous conditionsby treatment with a suitable acid, such as trifluoroacetic acid. In thehydrolysis of compounds of the formula VI, in particular, acid agentsare suitably used.

However, care must be taken in the hydrolysis that other substituentsare not attacked. Thus, the hydrolysis is advantageously carried outunder gentle conditions, for example by starting from starting compoundswhich are easily hydrolysable in the desired manner, for example fromthose of the formula VI, wherein Y denotes a divalent radical of analdehyde or of a ketone, and preferably using short reaction timesand/or mild hydrolysing agents. Prolonged heating in an acid medium canreduce the yields.

Radicals removable by ammonolysis are, in particular, functionallymodified carboxyl radicals, above all esterified carboxyl radicals, suchas alkoxycarbonyl radicals, or acid anhydride radicals, such ashalogenocarbonyl radicals, for example the chlorocarbonyl radical.Further starting materials containing radicals removable by ammonolysisare also compounds of the formula VI, wherein Py, Ph and R₂ have theindicated meanings and Y represents the carbonyl or thiocarbonylradical.

The ammonolysis can be carried out in the usual manner, for example bymeans of an amine which carries at least one hydrogen atom on thenitrogen atom, such as a mono- or di-lower alkylamine, for examplemethylamine or dimethylamine, or especially by means of ammonia,preferably at elevated temperature. Instead of ammonia it is alsopossible to use an agent which gives off ammonia, such ashexamethylenetetramine.

Radicals removable by reduction are, for example, α-arylalkyl radicals,such as benzyl radicals, or 60 -aralkoxycarbonyl radicals, such asbenzyloxycarbonyl radicals, which can be split off in the usual mannerby hydrogenolysis, especially by catalytically activated hydrogen, suchas by hydrogen in the presence of a hydrogenation catalyst, for exampleplatinum, palladium or Raney nickel. Examples of further radicals whichcan be split off by hydrogenolysis are 2-halogenoalkoxycarbonylradicals, such as the 2,2,2-trichloroethoxy-carbonyl radical or the2-iodoethoxy-carbonyl or 2,2,2-tribromoethoxy-carbonyl radical, whichcan be split off in the usual manner, especially by metallic reduction(so-called nascent hydrogen). Nascent hydrogen can be obtained by theaction of metal or metal alloys, such as amalgams, on agents whichprovide hydrogen, such as carboxylic acids, alcohols or water, and inparticular, zinc or zinc alloys together with acetic acid can be used.The hydrogenolysis of 2-halogeno-alkoxycarbonyl radicals can also beeffected by chromium-(II) compounds, such as chromium-(II) chloride orchromium-(II) acetate. A radical removable by reduction can also be anarylsulphonyl group such as the toluenesulphonyl group, which can beremoved, in particular removed from a N atom, in the usual manner byreduction with nascent hydrogen, for example by means of an alkalimetal, such as lithium or sodium, in liquid ammonia.

A further possible procedure is to reduce a Schiff's base correspondingto the formula I, wherein the N atom is doubly bonded to a substituentR₁ or R₂ or to the propoxy part and optionally carries a positivecharge, or a tautomer or hydrate thereof.

For example, a possible procedure is to reduce a Schiff's base of theformula VIIa, VIIb, VIII a or VIIIb

    Py-Ph-O-CH.sub.2 -CHOH-CH=N-R.sub.2                        (VII a) ##STR5##

    Py-Ph-O-CH.sub.2 -CHOH-CH.sub.2 -N=R.sub.2 '               (VIIIa) ##STR6## or a ring tautomer of the formula IXa or IXb corresponding to the formula VIIIa or VIIIb ##STR7## wherein Py, Ph, R.sub.1 and R.sub.2 have the above meanings and R.sub.2 ' H is the same as R.sub.2, it also being possible for compounds of the formulae VIII and IX to be present alongside one another.

The reduction can be carried out in the usual manner, for example bymeans of hydrogen in the presence of a hydrogenation catalyst, such asnickel, platinum or palladium, for example Raney nickel, platinum blackor palladium on active charcoal. Optionally, the hydrogen uptake isfollowed volumetrically and the hydrogenation is discontinued after thecalculated amount of hydrogen has been taken up. The reduction can,however, also be effected with, for example, formic acid or a hydridereducing agent, such as with hydrides, for example simple or complexhydrides, such as with a borane, for example diborane, or with a complexdi-light metal hydride, for example with an alkali metal-aluminiumhydride, such as lithium aluminium hydride, sodium aluminium hydride orsodium tris-(2-dimethylaminoethoxy)-aluminium hydride or sodiumcyanoborohydride.

A further possible procedure is to react a compound of the formula X##STR8## with a γ-oxo-lower alkanone or a tautomer or functionalderivative thereof.

A γ-oxo-lower alkanone, a tautomer or a functional derivative can be inthe monomeric or in the polymeric form. A functional derivative can beopen-chain or cyclic, such as an open-chain or cyclic acetal, ketal oracylal or an open-chain or cyclic α-halogeno-ether, enol-ether orenolester. A γ-oxo-lower alkanone can also be present as a mixture withits tautomer and/or its functional derivatives. As examples of suitableγ-oxo-lower alkanones there may be mentioned: Succinaldehyde,2-methyl-succinaldehyde, 2,3-dimethyl-succinaldehyde, levulinaldehyde,4-oxo-hexaldehyde and 2,5-hexanedione. As examples of suitablederivatives of γ-oxo-lower alkanones there may be mentioned: Monomericacetals of succinaldehyde, such as succinaldehyde-monodiethylacetal,-bis-dimethylacetal, and -bis-diethylacetal, acylals such assuccinaldehyde-1,1,-diacetate (4,4-diacetoxybutyraldehyde), enol-etherssuch as 1,4-diphenoxy-butadiene and enol-esters such as1,4-diacetoxy-butadiene. Further suitable compounds are, for example,derivatives of tetrahydrofurane, which react, for example, like theacetals or acylals of succinaldehyde or like open-chainα-halogenoethers. Such compounds are, for example, optionally loweralkyl-substituted 2,5-dialkoxytetrahydrofuranes and related compounds,such as 2,5-dimethoxy-, 2,5-diethoxy-, 2,5-dipropoxy-, 2,5-dibutoxy-,2,5-bisallyloxy, 2,5-bis-(2-chloroethoxy)-, 2,5-diphenoxy- and2,5-bis-(3,4-xylyloxy)tetrahydrofurane,2-methyl-2,5-dimethoxy-tetrahydrofurane and3-methyl-2,5-dimethoxy-tetrahydrofurane, and also2,5-diacyloxy-tetrahydrofuranes, such as 2,5-diacetoxy-tetrahydrofurane,as well as 2,5-dihalogeno-tetrahydrofuranes, such as2,5-dichloro-tetrahydrofurane and 2,5-dibromotetrahydrofurane, and alsocompounds which are simultaneously to be classified under two types,such as 2-chloro-5-(2-chloroetoxy)-tetrahydrofurane and 2-allyloxy-5-chloro-tetrahydrofurane.

Polymeric compounds of the abovementioned nature are obtained, forexample, when polymeric aldehydes, such as polymeric succinaldehyde, arereacted with amounts of acetalising or acylating materials, or mixturesof materials, which are less than equivalent to the succinaldehyde unitspresent.

The reaction of a compound X with a γ-oxo-lower alkanone, a tautomerthereof or a functional derivative thereof, can be carried out in theusual manner, especially warm, such as at about +30° to +140° and in thepresence or absence of a diluent and/or condensation agent.

Suitable media for the reaction according to the invention are, whenusing a free γ-oxo-lower alkanone, any solvent in which this compound issoluble, for example lower alkanols, such as methanol and ethanol, orlower alkanecarboxylic acids, such as acetic acid. Acetals and acylalsof the γ-oxo-lower alkanones, as well as cyclic acetal-like derivativesare advantageously reacted in lower alkanecarboxylic acids, such asacetic acid, as the solvent and condensation agent, or in the presenceof catalytical amounts of an acid condensation agent, such as p-toluenesulphonic acid, in the presence of absence of an inert organic solventor diluent, such as, for example, benzene, toluene, o-dichloribenzene oracetonitrile. The reaction of α-halogeno-ethers is carried out, forexample, in inert organic solvents, such as halogeno-lower alkanes, forexample chloroform or the abovementioned solvents. The reactiontemperature is preferably between room temperature and the boiling pointof the solvent or diluent used, for example +25° to +140°, the lowestrange in particular being relevant to the last-mentioned halogencompounds.

In resulting compounds, it is possible, within the scope of thedefinition of the end products, to modify, introduce or removesubstituents in the usual manner, or to convert resulting compounds inthe usual manner into other end products.

Thus, it is possible, in resulting compounds, to hydrolyse functionallymodified carboxyl groups, as a constituent of R₂, to free carboxylgroups in the usual manner, preferably in the presence of a strong base,such as a strong organic or, above all, inorganic base, preferably ametal base, for example an alkaline earth metal or alkali metalcarbonate or, above all, hydroxide, for example calcium hydroxide,sodium hydroxide or potassium hydroxide, or in the presence of a strongacid, for example a strong mineral acid, especially a hydrogen halideacid, for example hydrochloric acid or above all hydrobromic acid, orsulphuric acid. If desired, oxidising agents such as nitrous acid, canbe added when hydrolysing the carbamoyl group.

The nitrile group as a constituent of R₂ can also be hydrolysed to thecarbamoyl group in the usual manner, for example as described above forthe hydrolysis to the free carboxyl group. Equally, it is also possibleto convert the carbamoyl group into the nitrile group by dehydration inthe usual manner, for example by heating and/or by the action ofdehydrating agents.

Free carboxyl groups as a constituent of R₂ can be esterified in theusual manner, for example by reaction with a corresponding alcohol,preferably in the presence of an acid, such as a mineral acid, forexample sulphuric acid or hydrochloric acid, or in the presence of awater-binding agent, such as dicyclohexylcarbodiimide, or by reactionwith an appropriate diazo compound, for example a diazoalkane. Theesterification can also be carried out by reaction of a salt, preferablyan alkali metal salt, of the acid with a reactively esterified alcohol,for example a halide, such as the chlorine, of the correspondingalcohol.

Free carboxyl groups can also be converted into amidised carboxyl groupsin the usual manner, for example by reaction with ammonia or a primaryor secondary amine and, if necessary, dehydration of the ammonium saltformed as an intermediate.

Free carboxyl groups can, for example, also be converted into acidhalide or acid anhydride groups in the usual manner, for example byreaction with halides of phosphorus or sulphur, such as thionylchloride, phosphorus pentachloride or phosphorus tribromide, or withacid halides, such as chloroformic acid esters or oxalyl chloride. Theacid anhydride or acid halide groups can then be converted intoesterified carboxyl groups in the usual manner by reaction withcorresponding alcohols, if desired, in the presence of acid-bindingagents, such as organic or inorganic bases.

Functionally modified carboxyl groups as a constituent of R₂ canfurthermore be converted into esterified or amidised carboxyl groupsaccording to customary methods. Thus, resulting acid anhydrides, such asacid halides, for example acid chlorides, or ketones can be convertedinto esters or amides by reactions with, respectively, an alcohol orammonia or a primary or secondary amine, if desired in the presence ofacid-binding agents, such as organic or inorganic bases. Resultingnitriles can also be converted analogously by reaction with an alcoholinto the corresponding imino-ethers which can be hydrolysed in the usualmanner to the corresponding esters.

The reactions mentioned an optionally be carried simultaneously orsuccessively and in any desired sequence.

The reactions mentioned are carried out in the usual manner in thepresence or absence of diluents, condensation agents and/or catalyticagents, at lowered, ordinary or elevated temperature, if appropriate ina closed vessel.

Depending on the process conditions and starting materials, the endproducts are obtained in the free form or in the form of their acidaddition salts which is also encompassed by the invention. Thus, forexample, basic, neutral or mixed salts and possibly also hemihydrates,monohydrates, sesquihydrates or polyhydrates thereof can be obtained.The acid addition salts of the new compounds can be converted into thefree compound in a manner which is in itself known, for example by meansof basic agents, such as alkalis or ion exchangers. On the other hand,the resulting free bases can form salts with organic or inorganic acids.Acids used for the manufacture of acid addition salts are especiallythose which are suitable for forming therapeutically usuable salts. Asexamples of such acids there may be mentioned: Hydrogen halide acids,sulphuric acids, phosphoric acids, nitric acid, perchloric acid,aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids orsulphonic acids, such as formic acid, acetic acid, propionic acid,succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvicacid, fumaric acid, benzoic acid, anthranilic acid, p-hydroxybenzoicacid or salicyclic acid, embonic acid, methanesulphonic acid,ethanesulphonic acid, cyclohexanesulphonic acid, hydroxyethanesulphonicacid and ethylsulphonic acid, halogenobenzenesulphonic acids,toluenesulphonic acid, naphthalenesulphonic acid or sulphanilic acid,methionine, tryptophane, lysine or arginine.

Acid compounds can furthermore be in the free form or in the form oftheir salts with bases, such as alkali metal salts or alkaline earthmetal salts, salts with ammonia or salts with amines. Suitable compoundsfor the manufacture of salts with bases are, for example, alkali metal,such as sodium or potassium, carbonates, bicarbonates or hydroxides, orcorresponding alkaline earth metal compounds, such as calcium ormagnesium compounds, or ammonia, as well as amines, such as aliphaticamines, for example lower alkylamines, such as trimethylamine ortriethylamine. Aluminium salts, for example salts of two mols of acidand one mol of aluminium hydroxide, are also suitable, especiallybecause of their slower resorption, absence of odour and the fact thatthey cause little gastro-intestinal disturbance.

These or other salts of the new compounds such as, for example, thepicrates, can also be used to purify the resulting free bases, byconverting the free compound into salts, isolating these and againliberating the compound from the salts. Because of the closerelationships between the new compounds in the free form and in the formof their salts, the free compounds are, in the preceding and followingtext, where appropriate also to be understood to include thecorresponding salts, with regard to general sense and intended use.

The invention also relates to those embodiments of the process accordingto which a compound obtainable as an intermediate product at any stageof the process is used as the starting material and the missing processsteps are carried out, or the process is discontinued at any stage, orin which a starting material is formed under the reaction conditions orin which a reactant is in the form of its salts, if relevant.

Thus, a possible procedure is to react an aldehyde of the formula XI

    Py-Ph-O-CH.sub.2 -CHOH-CHO                                 (XI)

with an amine HNR₁ R₂, wherein Py, Ph, R₁ and R₂ have the abovemeanings, in the presence of a suitable reducing agent, such as one ofthose mentioned above. In this case, a compound of the formula VIIa orVIIb is used as an intermediate product and is then reduced inaccordance with the invention.

A further suitable procedure is to react an amine of the formula XII

    Py-Ph-O-CH.sub.2 -CHOH-CH.sub.2 -NH.sub.2                  (XII)

with an aldehyde or ketone of the formula O=R₂, wherein Py, Ph and R₂have the above meaning, in the presence of a suitable reducing agent,such as one of those mentioned above. This gives, as the intermediateproduct, a compound of the formula VIIIa or VIIIb or IXa or IXb, whichis then reduced in accordance with the invention.

A further suitable procedure is to heat a compound of the formula X withan α,β,γ,δ-tetrahydroxy-ε-carboxylower alkanecarboxylic acid, such asmucic acid or saccharic acid, with elimination of carbon dioxide andwater. Hereupon, a γ-oxo-lower alkanone or a tautomer thereof isobtained as an intermediate product and then reacts further according tothe invention. The heating is preferably carried out to between about+100° and +300° in the presence or absence of inert organic solvents ofmedium or fairly high boiling point or boiling range such as, forexample, xylenes, xylene mixtures or diethylene glycol dimethyl ether.The reaction to give a compound I can also proceed through thedecarboxylation partially only occurring after the cyclisation to thepyrrole has taken place, so that after the reaction has taken place anycarboxyl groups still present are finally split off as carbon dioxide bystronger heating. It is also advantageously possible to convert a mucicacid or saccharic acid salt of a compound X into compounds I by drydistillation sublimation, the pressure being reduced, if appropriate, insuch a way as to give a favourable reaction temperature.

Depending on the choice of the starting materials and procedures, thenew compounds can be in the form of optical antipods or racemates, or ifthey contain at least two asymmetric carbon atoms, also as racematemixtures and/or as pure geometrical isomers or as mixtures thereof(isomer mixtures).

Resulting isomer mixtures can be separated into the two pure geometricalisomers in a known manner on the basis of the physico-chemicaldifferences of the constituents, for example by chromatography on asuitable stationary phase, such as silica gel, or aluminium oxide, whichhave been pretreated with a complex-forming heavy metal compound, forexample with a silver compound, or by forming a heavy metal additioncompound, for example the silver nitrate complex, separating this intothe addition compounds of the pure isomers, for example by fractionalcrystallisation and subsequently liberating the pure isomers.

Racemate mixtures can be separated into the two stereoisomeric(diastereomeric) pure racemates in a known manner on the basis of thephysico-chemical differences of the constituents, for example bychromatography and/or fractional crystallisation.

Resulting racemates can be separated into the diastereomers according toknown methods, for example by recrystallisation from an optically activesolvent, with the aid of micro-organisms or by reaction with anoptically active acid which forms salts with the racemic compound andseparation of the salts obtained in this manner, for example on thebasis of their different solubilities, and the antipods can be liberatedfrom the diastereomers by the action of suitable agents. Particularlycustomary optically active acids are, for example, the D- and L- formsof tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid,camphorsulphonic acid or quinic acid. Advantageously, the more activeL-antipode is isolated.

Appropriately, the starting materials used for carrying out thereactions according to the invention are those which lead to theinitially particularly mentioned groups of end products and especiallyto the end products which have been particularly described or singledout.

The starting materials are known or can, if they are new, be obtainedaccording to methods which are in themselves known.

Compounds of the formula II can be manufactured, for example, in theusual manner, from a phenol Py-Ph-OH or a phenolate thereof, by means ofepichlorohydrin or the like. Compounds of the formula V can bemanufactured, for example, in the usual manner from an amine NHR₁ R₂ andepichlorohydrin or the like. Compounds of the formula I with removableradicals on the amino group and/or hydroxyl group can, for example, bemanufactured in the usual manner from a phenol Py-Ph-OH or a phenolatethereof and an appropriately substituted compound of the formula V.Compounds of the formula X can be manufactured, for example, in theusual manner from a phenol H₂ N-Ph-PH or a phenolate thereof, by meansof a compound of the formula V. Compounds of the formula XI can bemanufactured, for example, in the usual manner from a phenol Py-PH-OH ora phenolate thereof and 2,3-epoxy-propionaldehyde. Compounds of theformula XII can be manufactured, for example, in the usual manner from aphenol Py-Ph-OH or a phenolate thereof and 2,3-epoxy-n-propylamine.

The new compounds can be used as medicaments, for example in the form ofpharmaceutical preparations, in which they or their salts are present asa mixture with a pharmaceutical, organic or inorganic, solid or liquidexcipient suitable for enteral or parenteral administration. Suitablematerials for forming the excipient are those which do not react withthe new compounds such as, for example, water, gelatine, lactose,starch, magnesium stearate, talc, vegetable oils, benzyl alcohols,rubber, polyalkylene glycols, white petroleum jelly, cholesterol orother known medicinal excipients. The pharmaceutical preparations canbe, for example, in the form of tablets, dragees, capsules orsuppositories or in a liquid form, as solutions (for example as anelixir or syrup), suspensions or emulsions. They are optionallysterilised and/or contain auxiliaries, such as preservatives,stabilisers, wetting agents or emulsifiers, salts for regulating theosmotic pressure or buffers. They can also contain yet othertherapeutically valuable materials. The preparations, which can also beused in veterinary medicine, are formulated according to customarymethods.

The examples which follow illustrate the invention without, however,restricting it.

EXAMPLE 1

10 g (0.047 mol) of 1-[4-pyrrolyl-(1)-phenoxy]-2,3-epoxy-propane aredissolved in 100 ml of isopropanol, 4.25 ml (0.05 mol) of isopropylamineare added and the mixture is then heated to the boil for 3 hours underreflux. It is then evaporated in vacuo and the resulting crude base iscrystallised from ethyl acetate.1-[4-Pyrrolyl-(1)-phenoxy]-2-hydroxy-3-isopropylamino-propane isobtained, of which the hydrochloride, prepared from a solution of thebase in methanol and a solution of hydrogen chloride in ether, melts at208°-210° C.

The starting material can be prepared as follows:

5.0 g (31.4 mmols) of 4-pyrrolyl-(1)-phenol, 11.6 g (9.9 ml) ofepichlorohydrin and 0.1 ml of piperidine are heated for 6 hours underreflux. Instead of the piperidine, a small amount of potassium carbonateand acetonitrile can also be used. The excess epichlorohydrin is thendistilled off and the residue is distilled at 160° C and 0.05 mm Hg. Theresulting 1-[4-pyrrolyl-(1)-phenoxy]-2,3-epoxy-propane can be usedfurther direct. The 4-pyrrolyl-(1)-phenol used can, in turn, be obtainedfrom p-aminophenol and 2,5-dimethoxy-tetrahydrofurane in glacial aceticacid.

EXAMPLE 2

40 g (0.18 mol) of1-(4-amino-phenoxy)-2-hydroxy-3-isopropylamino-propane and 25 g (0.189mol) of 2,5-dimethoxy-tetrahydrofurane in 400 ml of glacial acetic acidare heated for 11/2 hours under reflux. The acetic acid is distilled offunder reduced pressure. The residue is dissolved in ethyl acetate andthe solution is washed twice with sodium hydroxide solution and twicewith water. The ethyl acetate phase is dried over magnesium sulphate,filtered and concentrated until crystallisation starts.1-[4-Pyrrolyl-(1)-phenoxy]-2-hydroxy-3-isopropylaminopropane isobtained.

The hydrochloride is obtained from the base by reacting a solution ofthe base in methanol with a solution of hydrogen chloride in ether. Thehydrochloride melts at 208°-210° C.

EXAMPLE 3

108 g (0.482 mol) of1-(2-amino-phenoxy)-2-hydroxy-3-isopropylamino-propane and 64 g (0.482mol) of 2,5-dimethoxy-tetrahydrofurane in 1,080 ml of glacial aceticacid are heated for 1 hour under reflux. The glacial acetic acid isdistilled off under reduced pressure. The residue is partitioned betweenethyl acetate and sodium hydroxide solution. The ethyl acetate phase iswashed once with sodium hydroxide solution and twice with water, driedover magnesium sulphate, filtered and concentrated. The residue obtainedis a dark brown oil which is taken up in ether and the ether solution isfiltered. The filtrate is evaporated under reduced pressure. The residueis again dissolved in ether, the solution is filtered and the filtrateis evaporated under reduced pressure. Light yellow crystals are thusobtained, which are recrystallised from ether/petroleum ether andconsist of1-[2-pyrrolyl-(1)-phenoxy]-2-hydroxy-3-isopropylamino-propane, meltingpoint 80°-81° C. With hydrogen chloride in methanol, the hydrochlorideis obtained, which after recrystallisation from isopropanol melts at(129° C) 130°-131° C.

The starting material can be prepared as follows: 290 g (1.14 mol) of1-(2-nitro-phenoxy)-2-hydroxy3-isopropylamino-propane are dissolved in1.5 l of ethanol.

280 ml (5.7 mols) of hydrazine hydrate are added to the solution. About100 ml of this solution are introduced into a flask and warmed to about70° C. Raney nickel is then added in portions. The remainder of thesolution is then allowed to run in in such a way that the temperature iskept at about 70° C (reflux) by the heat of reaction. After completionof the addition, the mixture is stirred for a further hour and isfiltered after it has cooled. The filtrate is concentrated until itcrystallises and 1-(2-amino-phenoxy)-2-hydroxy-3-isopropylamino-propaneof melting point 94°-97° C is thus obtained.

EXAMPLE 4

Tablets containing 60 mg of active substances are prepared in the usualmanner, to have the following composition:

    ______________________________________                                        Composition                                                                   1-[4-Pyrrolyl-(1)-phenoxy]-2-hydroxy-3-                                       isopropylamino-propane hydrochloride                                                                     60 mg                                              Wheat starch               59 mg                                              Lactose                    60 mg                                              Colloidal silica           10 mg                                              Talc                       10 mg                                              Magnesium stearate         1 mg                                                                          200 mg                                             ______________________________________                                    

Preparation

The 1-[4-pyrrolyl-(1)-phenoxy]-2-hydroxy-3-isopropylamino-propanehydrochloride is mixed with a part of the wheat starch, with lactose andwith colloidal silica and the mixtue is forced through a sieve. Afurther part of the wheat starch is worked into a paste with a 5-foldamount of water on a waterbath and the powder mixture is kneaded withthis paste until a slightly plastic mass has been produced.

This plastic mass is forced through a sieve of approx. 3 mm mesh widthand dried, and the resulting dry granules are again forced through asieve. The remaining wheat starch, talc and magnesium stearate are thenmixed in and the mixture is pressed to give tablets weighing 200 mg andhaving a breaking groove. The daily dose is about 1/2 to 4 tablets inthe case of a warm-blooded animal of about 75 kg body weight, it alsobeing possible to administer the corresponding dose of active compoundas a single tablet of appropriate composition.

Tablets containing 60 mg of1-[2-pyrrolyl-(1)phenoxy]-2-hydroxy-3-isopropyl-amino-propanehydrochloride as the active compound can be prepared analogously.

EXAMPLE 5

52 ml of tert.butylamine are added to a solution of 26.9 g of1-[o-(pyrrolyl-1-yl]-2,3-epoxy-propane in 250 ml of isopropanol and themixture is heated to the boil under reflux for 11/2 hours. The oil whichremains after evaporating off the volatile constituents in vacuo isdistilled in a high vacuum in a bulb tube and gives1-tert.butylamino-3-[o(pyrrol-1-yl)-phenoxy]-2-propanol as a colourlessoil of boiling point 130°-140° C/0.04 mm Hg. With half the equivalentamount of fumaric acid, this forms a neutral fumarate of melting point203°-204° C (from methanol).

The starting material can be prepared as follows:

a. 109 g of o-aminophenol and 132 g of 2,5-dimethoxy-tetrahydrofurane in700 ml of glacial acetic acid are heated to the boil for 30 minutes.After cooling, the reaction mixture is filtered and the polymericmaterial is thus removed. The filtrate is evaporated in vacuo, theresidue is dissolved in approx. 1 liter of ethyl acetate and thesolution is washed with 200 ml of water. The dark oil which remainsafter drying and evaporating the organic phase is distilled in a bulbtube under a high vacuum. This gives o-(pyrrol-1-yl)-phenol of boilingpoint 115°-125° C/0.05 mm Hg gives an oil which gradually crystallisesand melts at 46°-49° C.

b. 95.7 g of o-(pyrrol-1-yl)-phenol, 245 g of potassium carbonate and167 g of epichlorohydrin are heated to the boil in a nitrogenatmosphere, whilst stirring. After 6 hours, the reaction mixture iscooled and filtered and the filtrate is evaporated in vacuo, ultimatelyat a bath temperature of 120° C. The oil which remains is dissolved in300 ml of ether and the solution is extracted with 300 ml of 2 N sodiumhydroxide solution and washed with 100 ml of water. The oil whichremains after evaporating off the solvent is distilled in a high vacuumand gives 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane of boiling point103°-105° C/0.001 mm Hg.

EXAMPLE 6

50 ml of isopropylamine are added to a solution of 26.9 g of1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane in 250 ml of isopropanoland the mixture is heated to the boil under reflux for 11/2 hours. Theoil which remains after evaporating off the volatile constituents invacuo is distilled in a bulb tube under a high vacuum and gives1-iso-propylamino-3]-o(pyrrol-1-yl)-phenoxy]-2-propanol as a colourlessoil of boiling point 125°-135° C/0.04 mm Hg. The distillate whichcrystallises can be recrystallised from ether/petroleum ether and givescrystals of melting point 80°-81° C and is in every respect identicalwith the product obtained in Example 3.

EXAMPLE 7

A solution of 15 g of 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane and7 g of morpholine in 150 ml of isopropanol is heated for 2 hours to theboil under reflux. After evaporation in vacuo, an oil remains, whichcrystallises and after recrystallisation from butanone gives1-morpholino-3-[o-(pyrrol-1-yl)-phenoxy]-2-propanol of melting point81°-82° C. It forms a neutral fumarate of melting point 136°-137° C(from butanone).

EXAMPLE 8

30 g of 1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane,dissolved in 200 ml of isopropanol, are mixed with 60 ml ofisopropylamine and the mixture is heated to the boil under reflux for 2hours. The oil which remains after evaporation is recrystallised frompetroleum ether with addition of active charcoal and gives1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-3-isopropylamino-2-propanol ofmelting point 73°-75° C. Its neutral fumarate melts at 186°-188° C (fromacetone).

The starting materials required can be prepared analogously to Example5:

a. o-Aminophenol and 2,5-hexanedione giveo-(2,5-dimethyl-pyrrol-1-yl)-phenol of melting point 95°-99° C.

b. o-(2,5-Dimethyl-pyrrol-1-yl)-phenol and epichlorohydrin give1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane of boilingpoint 120°-122° C/0.08 mm Hg.

What we claim is:
 1. Pyrrolyl compounds of the formula I ##EQU2##wherein Py is 1-pyrrolyl or mono- or di-lower alkylated 1-pyrrolyl, Phis phenylene, R₁ is hydrogen or lower alkyl and R₂ is hydrogen, loweralkyl, phenyl-lower alkyl having up to 10 carbon atoms wherein thephenyl ring is unsubstituted or mono-substituted by lower alkyl, loweralkoxy, halogen or trifluoromethyl, or R₁ and R₂ together are loweralkylene, their antipodes and salts.
 2. Pyrrolyl compounds of theformula I

    Py-Ph-O-CH.sub.2 -CHOH-CH.sub.2 -NH-R.sub.2                (I)

wherein Py is 1-pyrrolyl or mono- or di-lower alkylated 1-pyrrolyl, Phis phenylene and R₂ is lower alkyl, their optical antipodes and salts.3. A compound as claimed in claim 2 having the formula I wherein Py is1-pyrrolyl or 2,5-dimethyl-1-pyrrolyl, Ph is phenylene and R₂ is loweralkyl, their optical antipodes and salts.
 4. A compound as claimed inclaim 2 having the formula I wherein Py is 1-pyrrolyl or2,5-dimethyl-1-pyrrolyl, Ph is ortho- or para-phenylene and R₂ is loweralkyl, their optical antipodes and salts.
 5. A compound as claimed inclaim 2 having the formula I wherein Py is 1-pyrrolyl or2,5-dimethyl-1-pyrrolyl, Ph is ortho- or para-phenylene and R₂ ismethyl, ethyl, isopropyl or tert.-butyl, their optical antipodes andsalts.
 6. A compound as claimed in claim 2 having the formula I which is1-[4-pyrrolyl-(1)-phenoxy]-2-hydroxy-3-isopropylamino-propane, itsoptical antipodes and salts.
 7. The hydrochloride salt of the compoundof claim
 6. 8. A compound as claimed in claim 2 having the formula Iwhich is 1-[2-pyrrolyl-(1)-phenoxy]-2-hydroxy-3-isopropylamino-propane,its optical antipodes and salts.
 9. The hydrochloride salt of thecompound of claim
 8. 10. A compound as claimed in claim 2 having theformula I which is1-tert.-butylamino-3-[o-pyrrol-1-yl)-phenoxy]-2-propanol, its opticalantipodes and salts.
 11. The neutral fumarate salt of the compound ofclaim
 10. 12. A compound as claimed in claim 9 having the formula Iwhich is1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-3-isopropylamino-2-propanol,its optical antipodes and salts.
 13. The neutral fumarate salt of thecompound of claim 2.